Method and system for tissue imaging and analysis

ABSTRACT

A method for detecting abnormal tissue in a region of healthy tissue, comprising: 
     a) making a first measurement of ultrasound backscattered from the region;
         b) heating the region, at least after the first measurement;   c) making one or more additional measurements of ultrasound backscattered from the region after some or all of the heating; and   d) analyzing the measurements to detect the abnormal tissue by finding one or both of differences in changes in temperature and differences in thermal expansion, caused by the heating, between the abnormal tissue and the healthy tissue.

RELATED APPLICATIONS

This application is a National Phase of PCT Patent Application No.PCT/IB2010/056117 having International filing date of Dec. 29, 2010,which is a continuation-in-part (CIP) of U.S. patent application Ser.Nos. 12/648,440 and 12/648,433, both filed on Dec. 29, 2009. U.S. patentapplication Ser. No. 12/648,440 claims the benefit of priority under 35U.S.C. §119(e) from U.S. Provisional Patent Application No. 61/193,829filed on Dec. 29, 2008, . U.S. patent application Ser. No. 12/648,433claims the benefit of priority under 35 U.S.C. §119(e) from U.S.Provisional Patent Application Nos. 61/182,781 filed on Jun. 1, 2009,and 61/193,815 filed on Dec. 29, 2008. The contents of all the aboveapplication are incorporated herein by reference as if fully set forthherein.

PCT Patent Application No. PCT/IB2010/056117 is also related to PCTPatent Application No. PCT/IB2010/056116 filed on Dec. 29, 2010, thecontents of which are incorporated herein by reference as if fully setforth herein.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to measuring backscatter waveformsbehavior in time due to ultrasound excitement of tissue to determinetissue type or substance composition, and more particularly, to amethod, and corresponding device and system thereof, using ultrasoundwaves for tissue substance differential excitation, that createsdifferent scattering behavior changes when exciting different tissues orsubstances; and measuring the backscatter waveform behavior before,while, and/or after excitation periods, at one or more locations in thetissue, and measuring gradients of this behavior, to image the examinedarea and/or determine tissue types or substance compositionirregularities.

There are many situations where it is necessary or desirable to identifytissue nature and substance in an organ. One example of such a situationis the identification of malignant areas within the body of a patient,where it is required to first find the exact location of suspectedcancerous region for sampling, and then indicate whether the suspectedlocation is in fact cancerous, and if so of what malignant nature. Othersuch situations include the ability to visualize a map of tissue typesor substance composition for medical imaging purposes. Yet anotherexample is the need for reading different substance levels within abody, such as glucose levels in the blood.

In these and other cases it is desirable to determine tissueirregularities for localizing suspected material, image tissues, oranalyze the tissue substance. It is also desirable to identify, or findthe probability of identification of, tissue as of knowncharacteristics.

Present techniques known from the prior art for determining tissue typeor substance include medical imaging, and tissue sampling such as ablood sample or to biopsy techniques. Imaging of tissue type orsubstance and irregularities include technologies such as X-Ray, MRI,PET, Ultrasound, and IR imaging. X-Ray based tomography uses high energyelectromagnetic radiation that is harmful to both patient and physician.This harmful effect substantially reduces the capacity of thistechnology to enable continues imagery. As X-Ray technology mainlymeasures acid levels in the examined area, it is limited to identifyingdesirable tissue differences where acid levels substantially differ. MRIuses high intensity magnetic fields. As such it yields very high cost ofownership. The need for very accurate magnetic field in MRI equipmentsubstantially limits the geometry of the equipment, not enablingdesirable physician interaction with the body of the patient ataffordable costs. PET technology is limited in its capacity to identifydesirable substance composition differences, and hence is used mainly inconjunction with other imaging techniques.

Ultrasound-diagnostics equipment mostly analyzes ultrasound waves'specular reflection; as such it is limited in its capacity to identifydesirable tissue substance as sonic echo does not differentiate wellenough between tissue materials. Table 1, a table of ultrasound speedand acoustic impedence for different soft tissues, taken from G. E. P.M. Van Venrooij, “Measurement of ultrasound velocity in human tissue,”Ultrasonics, October 1971, p. 240-242, shows that specular reflectioncoefficients, due to differences in acoustic impedance between softtissues, are typically only a few times 10⁻⁴, or less, which istypically below the noise level.

TABLE 1 Ultrasound velocity, density, characteristic impedance andreflection coefficient of normal brain tissue of some body fluids andbrain tumors Number of T measuring c error θ Z R Substance [° C.] pointsN [ms⁻¹] [%] [kgm⁻³] [10⁶ Nsm⁻³] [×10⁵] Source water (not 23.5 20 1493.50.1 997.41 1.4896 — θ from degassed) handbook of Chemistry and Physics1968/69 blood 23.2 10 1549.6 0.7 1036 1.605 3 Heparinised blood 24.2 111556.4 0.3 1041 1.621 9 samples from blood {close oversize brace} 22.610 1570 1.5 1053 1.653 43 four different blood 22.4 12 1565 8 1036 1.6211 patients CSF 24.4 9 1515 3 1006 1.524 47 Fresh samples CSF {closeoversize brace} 25 11 1509.5 0.5 1006 1.519 54 from three CSF 21.8 111499 2 1005 1.506 62 different patients meningioma 19 20 1524.2 0.4 — —— After three hours immersion in formaline meningioma 19.8 20 1524.5 0.51031 1.572 0.3 After forty-eight hours immersion in formaline ependymoma20 18 1501 3 1024 1.537 17 Formalised astrocytoma 24.9 27 1517 8 10791.64 18 samples glioma 22.3 17 1500 3 1026 1.539 22 glioma 22.2 201529.1 0.6 1021 1.561 6 Fresh samples astrocytoma 27.5 41 1545.4 0.4 — —— meningioma 19.7 20 1557 2 — — — Five different meningioma 19.7 20 15461 — — — slides of one meningioma {close oversize brace} 19.7 21 1569 2 —— — tumour meningioma 19.7 14 1548 2 — — — meningioma 19.7 14 1569 2.5 —— —

Advanced ultrasound techniques use other characteristics of the echoreflectance in the body, such as ultrasonic backscatter of power wavesfor elasticity measurement, however those too are not sufficient forclear differentiation between different tissue types or substances inthe examined organs.

Arthur et al, in a talk “Change in Ultrasonic Backscattered Energy forTemperature Imaging: Factors Affecting Temperature Accuracy and SpatialResolution in 3-D,” presented at the 32^(nd) UITC, Alexandria, Va., May16, 2007, describe tests they did to develop a technique for usingchanges in backscattered energy of ultrasound to produce 3-D temperaturemaps in soft tissue, in order to monitor hyperthermia cancer treatment.The authors calculate theoretically that the standard deviation inbackscattering energy, from place to place in a liver tissue sample withmany small inclusions of aqueous or lipid material, increasesmonotonically with temperature, and they present in vitro test resultswith samples of bovine liver, turkey breast, and pork muscle, thatconfirm their calculations. They predict that it should be possible touse this technique to measure temperature to within 0.5 degrees Celsius,with a spatial resolution of 1 cm, for some kinds of tissue, if thetissue is calibrated.

Seip and Ebbini, “Noninvasive Estimation of Tissue Temperature Responseto Heating Fields Using Diagnostic Ultrasound,” IEEE Transactions onBiomedical Engineering, vol 42, pp. 828-839 (1995), describe anothertechnique for using backscattering of diagnostic ultrasound to monitortemperature changes in tissue. The technique is based on the observationthat most biological tissues are semi-regular scattering lattices.Muscle tissue, for example, may have a semi-regular lattice structuredue to individual muscle fibers, with spacing on the order of 1 mm.These lattice structures produce harmonics in the backscatteredultrasound, with the frequency shift of the harmonics depending ontemperature, through the temperature dependence of the sound speed, andthe thermal expansion of the lattice structure. If the temperaturedependence of the sound speed, and the thermal expansion coefficient,are known for the type of tissue being tested, then changes in thefrequency shift can be used to measure changes in temperature.Autoregressive model-based methods are used to estimate the frequencyshift. The authors state that temperature can be measured, using thistechnique, to within 0.4 degrees Celsius, with a spatial resolution of 1mm. To achieve this precision, the lattice spacing, the temperaturedependence of sound speed, and the thermal expansion coefficient of thetissue must all be known a priori. However, the technique could still beused to measure a relative temperature response, even if the temperaturedependence of sound speed and the thermal expansion coefficient of thetissue are not known very accurately.

IR imagery is used to map the tissue's natural heat superficially,however due to the mammal natural heat control mechanisms, temperatureis equalized by in-vivo tissues as heat conduction and convection occurwithin the organ, hence this technology is very limited in its capacityto identify desirable tissue substance.

Other means of identifying tissue substance composition include samplingtissue out of the organ for analysis. These include blood samples,biopsy, and others. The limitation of such technologies is in the needto sample out tissue from the organs, sometimes without knowing whetherthe sample is taken from the correct position inside the organ. Otherlimitations are the required handling, and the fact it is analyzed outof the living organ after loosing some of its characteristics. Thesecurrently available techniques from the prior art hence enable less thandesirable functionality of real time imaging/identification ordifferentiation of in-vivo tissue. In particular, X-Ray harmful effectscould be substantially reduced if there was to exist a harmless methodfor imaging in-vivo tissue at high resolution, with flexible equipmentgeometry, at affordable costs. Additionally, it would be preferable ifthere was to exist a method and system for imaging of tissue that couldsubstantially differentiate between different tissues in an organ, andenable the identification of malignant tumors, or other irregularitiesin live tissue.

Blood sampling techniques known form the prior art are based on drawingof blood from the body and lack the ability of identifying the point intime where glucose levels non-linearly change from acceptable levels. Inparticular, the identification of time of change, could be significantlyenhanced if there was to exist a capacity to conduct on going monitoringof the glucose level with non-intrusive means.

US 2004/0030227 to Littrup et al describes a method for treating amedical pathology including receiving a first set of acoustic radiationscattered by a volume of tissue containing at least a portion of themedical pathology, and thereafter, changing a temperature of the volumeof tissue. The method also includes thereafter, receiving a second setof acoustic radiation scattered by the volume of tissue and localizingthe portion of the medical pathology from the first and second sets ofreceived acoustic radiation. Localizing the portion of the medicalpathology comprises identifying the medical pathology from differencesin the first and second sets of received acoustic radiation resultingfrom the change in temperature. In some embodiments, the change intemperature is produced by ultrasound heating. The method also includesinsonifying the portion of the medical pathology with sufficient energyto damage the portion of the medical pathology. Littrup et al alsodescribe heating breast tissue with RF power, and using thermoacousticcomputed tomography to detect tumors, relying on the greater heatingresponse of tumors over benign tissue.

U.S. Pat. No. 6,728,567 to Rather et al, which was a priority documentfor Littrup et al, describes using an array of ultrasound transducers,transmitting ultrasound through body tissue from different directions,to find the ultrasound absorption rate, the sound speed, and otherparameters, as a function of three-dimensional position in the bodytissue, using tomographic methods. The results are used to distinguishcancerous tissue from healthy tissue.

US 2009/0105588 to Emelianov et al, describes heating tissue withlasers, though ultrasound heating is mentioned as well, and usingultrasound to measure the temperature change and determine whether it isfat or muscle, from the fact that fat and muscle have different thermalexpansion coefficients, and different rates of change of sound speedwith temperature.

US 2008/0200795, to Steckner, describes applying ultrasound at the MRIresonance frequency while making an MR image, for example at 0.3 tesla,where the resonance frequency would fall within the available ultrasoundfrequency range. The motion of the tissue in the ultrasound fieldscauses motion artifacts which affect the contrast of the MR image.Differences in the contrast of the MR image at different locations canbe used to obtain information about the ultrasound absorption rate atdifferent locations, since motion artifacts will be reduced in locationswhere the ultrasound does not penetrate as far into the tissue, due togreater absorption of ultrasound.

US 2010/0092424 to Sanghvi et al, describes applying high intensityfocused ultrasound to a tumor so that it releases cellular material, andexamining the released material to determine what kind of tumor it is.

U.S. Pat. No. 7,179,449 to Lanza et al, describes using an ultrasoundcontrast agent that binds to a target. The contrast agent has anultrasound reflectivity that is temperature dependent. By changing thetemperature, one can distinguish reflection of the ultrasound by thecontrast agent, from reflection of the ultrasound from other structuresin the body.

U.S. Pat. No. 6,824,518 to Von Behren et al, describes an ultrasoundimaging transducer that interleaves occasional high power pulses amongnormal imaging pulses, to improve image quality. The temperature ismonitored while using this transducer, to avoid damage to the tissue.

U.S. Pat. No. 5,935,075, to Casscells et al, describes using an infraredsensor in a catheter, in an IR fiberoptic system, optionally combinedwith an ultrasound image system, which detects plaque in arteries thatis likely to rupture, by the extra heat such plaque produces. The methodcan also detect abnormal tissue or a foreign body that is cooler thanthe surrounding tissue. Casscells et al cites an earlier patent, U.S.Pat. No. 4,986,671, that to describes a catheter with an infrared sensorfor measuring blood flow in a blood vessel. In U.S. Pat. No. 4,621,929,infrared radiation is directed along an optical fiber to heat aninfrared sensor, and its subsequent cooling rate is used to measure theblood flow.

US 2007/0106157 to Kaczkowski et al describes using backscatteredultrasound to map the temperature of tissue which has been heated usingultrasound, or using any other heat source, as a function of time. Thethermal diffusivity K, which can be anisotropic in regions of densevasculature, and the heat source Q, as functions of position, are thencalculated, and they are used for planning thermal therapy. Monitoringis done in real time, during thermal therapy, to see if Q has changed,due to changes in specific absorption, or changes in the interveningpath attenuation, and if so, changes can be made in the heating power inreal time, to compensate. Perfusion can also be measured non-invasively,and taken into account when monitoring the thermal therapy. Thesemethods “can also be utilized as a general tissue characterizationtechnique”, for modeling and monitoring thermal therapy.

U.S. Pat. No. 7,367,944 to Rosemberg et al describes monitoring aparameter indicating a biological response to heat, during thermaltherapy, and discusses the role of perfusion in heat transport duringthermal therapy.

US 2008/0004528 to Fitzsimmons et al describes using ultrasound todiagnose or characterize a target area by imaging it, to determine if itis benign or malignant, and to determine its size, geometry,vascularity, and/or density.

EP 1030611 to Baumgardner et al (CoolTouch, Inc.) describes diagnosticand therapeutic methods and techniques utilizing flushing and/orcooling, used in conjunction with energy delivery devices, includingultrasound. They describe sensing temperature, and using feedback loopsfor control. This is done when heating the dermis by a laser, whilecooling the epidermis, in order to remove wrinkles.

US 2009/0287082 to Lizzi et al describes using ultrasound imaging tomonitor heating and permanent effects in tissue, during application oftherapeutic ultrasound.

SUMMARY OF THE INVENTION

There is thus a need for, and it would be highly advantageous to have amethod, and corresponding device and system thereof, using ultrasonicdifferential backscatter analysis of ultrasound excited tissue in time,for mapping and/or identification of tissue to types or substancecomposition. Moreover, there is a need for such an invention whichachieves high resolution, accuracy, and precision.

Additionally there is a need for such an invention that would beharmless to both physician and patient, have flexible geometryrequirements enabling direct access of the physician to the patient, andenable real time imaging, and analysis of tissue types or substancecomposition for tissue imaging.

Additionally, there is a need for such an invention which is relativelyinexpensive to construct and implement, and which is especially suitablefor medical imaging.

Additionally, there is a need for such an invention which is relativelyinexpensive to construct and implement, and which is especially suitablefor medical analysis of in-vivo tissue.

Additionally, there is a need for such an invention which is generallyapplicable in blood glucose level monitoring.

Tissue substance behavior at ultrasonic excitation greatly varies atmany of its characteristics. Specifically, when excited at certainfrequencies, different tissues, and tissue barriers vary in theirultrasonic velocity, ultrasonic impedance, reflection coefficient, andother such parameters. In time, as energy is absorbed in the tissue, therate of change (gradient) of these variations in time, and specificallythe rate of change of the scattering coefficient, is also substantiallydifferent between tissues, and depends on the ultrasonic parametersduring excitation. It has been demonstrated in multiple experiments thatultrasonic parameters such as reflectance, and velocity of differenttissues greatly vary in biological tissues. It has also beendemonstrated that these change when under continuous tissue excitation,as a function of tissue type, ultrasonic duration, and the ultrasonicparameters exciting the tissue. The blood system, and other biologicalsystems equalize and regulate these changes in the tissues, and bringthem back to their original levels, but despite these mechanisms,differences in backscatter behavior are equalized only minutes afterultrasonic excitation ends. It has been demonstrated in many experimentsin the past, for example Arthur et al, and Seip and Ebbini, cited above,that the backscattering of ultrasonic waves is measurable, andachievable in high signal to noise ratios.

It is therefore clear from the above that it is both beneficial andpossible to determine tissue type or substance and/or irregularities byinducing ultrasonic energy for excitation of the examined area andmeasuring the backscattering behavior and gradients of tissue locationsfor such determination.

In an exemplary embodiment of the invention, ultrasound waves aretransmitted to the examined area. A portion of the waves' energy iscontinuously absorbed by the tissue material, heating it. Backscatter ofultrasound waves, either the ultrasound waves doing the heating, orother ultrasound waves used to measure the results of the heating,changes as a result of the heating. The change in backscatteringcharacteristics may depend on the type of tissue, and on whether it isnormal healthy tissue, or abnormal tissue such as cancerous tissue. Thismay be due to different tissues absorbing ultrasound differently, orthermally equilibrating at a different rate, resulting in a differentchange in temperature for different tissues, and it may also be due tothe backscattering characteristics of different tissues having differentdependence on temperature, for example different tissues may havedifferent thermal expansion coefficients. The change in temperature mayalso depend on the frequency or mix of frequencies of waves exciting thetissue, and the corresponding amplitudes, energy levels, and theduration of ultrasonic exposure, and these effects may also be differentfor different tissues. The behavior of tissue at each location ismeasured across time, and ultrasound backscatter characteristics, suchas amplitude of backscatter and the frequencies of harmonics in thebackscatter, and their gradients during the excitation process areusable for determining the tissue type or substance and/orirregularities of substance levels in the tissue. The present inventionis generally applicable for determining tissue material of a variety oforgans, and particularly applicable for imaging of tissue areas, theidentification of the location of suspected malignant (or otherirregular) material, or the identification, or likelihood ofspecification of the malignant material itself, or the identification,or likelihood of some substance dilution factor in tissue such asglucose in blood.

The present invention relates to a method, and corresponding device andsystem thereof, using measurement of backscatter behavior and itsgradients, from ultrasound excited tissue to image tissues of organs,and/or determine tissue irregularity, and/or determine tissue substancecomposition, or likelihood of being with a known substance, and/oridentify the substance. Ultrasonic waves at known frequency/frequencieswith to known amplitude/amplitudes are transmitted onto a body region.The transmitted ultrasonic waves gradually cause the reflectance andother ultrasonic coefficients to change, such that parameters(backscatter frequency shift, backscatter energy, etc.) are a functionof tissue substance and thermodynamic environment, frequency /frequencies of the transmitted waves, their amplitude, energy levels,and duration of the ultrasound waves. The backscattering shift andenergy behavior of the excited locations changes across time: before,while, and after the excitation period such that their gradient byitself, or coupled with other measurements (such as fluid movementmeasurement by the ultrasound specular reflection, Doppler effect, orother imaging device) is usable for determining tissue coefficients forimaging, and for determining tissue irregularities. The backscatteringbehavior is also usable for determining the likelihood of the locations'tissue of being with similar characteristics to known phenomenon such asa malignancy classification.

The present invention is generally applicable for imaging of theexamined area, for identifying tissue irregularities and/or theidentification of tissue material or suspected material type in theexamined locations. The present invention provides an accurate andprecise tissue inspection procedure. The present invention is generallyapplicable for identifying a biopsy location to verify biopsy sample isdrawn from the location of suspected malignancy/illness area; and/oridentify the type of tissue in the suspected area for its illness type;and/or indicate the likelihood of the sampled area as of being with oneor more characteristics/ malignancy/ illness. The present invention maybe usable in determining glucose level in the blood and/or determiningthe likelihood of this level being below a normal level, or being abovea certain level. The present invention is relatively inexpensive toconstruct and implement, and is especially suitable for application inhospital equipment, medical lab equipment, medical point of care, andprivate medical use.

Thus, according to an exemplary embodiment of the present invention,there is provided a method using ultrasonic backscatter waveformanalysis of ultrasonic excited areas for determining tissue type and orirregularity or substance level in the tissue, or likelihood of such alevel featuring the main steps of: (a) exposing the examined tissue areato ultrasonic waves or multiple ultrasonic waves, each with knowncharacteristics: (i) specific frequency (ii) specific amplitude (iii)specific energy (iv) specific duration; to such that the examined areais exited and as a result, parameters (ultrasonic backscatter patternand energy) of the examined area are a function of the substancematerial composition; (c) recording one or more backscatteringparameters: (i) ultrasound backscatter pattern (v) ultrasoundbackscatter energy at the required locations: (i) before (ii) while(iii) and after the ultrasound transmission. The parameters of thetransmitted ultrasound waves and the received parameters are usable for:(i) imaging of the examined area. (ii) identify or assess the likelihoodof an examined biopsy location of being of suspected material type orillness (iii) identifying irregular material of specific locations toidentify required position of a biopsy.

According to another aspect of the present invention there is provided adevice for differential excitation of tissues, herein, also referred toas the ultrasonic limited excitation device, that excites the diagnosedarea in energy levels adequate for overcoming the natural balancingsystems of the body, so as to create gradients in the scatteringbehavior of tissues in the examined area across more than 1% of eachsecond, and/or for more than 200 milliseconds. The device is limited inthe energy levels it transmits to the patient such that will not causeany harm or therapeutic effects, and hence is limited in not heating anyportion of the examined area with more than a preset of 1 degree Celsiusfrom its original temperature.

Alternatively, in another aspect of the present invention, there isprovided such an ultrasonic limited excitation device, preset for notheating any portion of the examined area with more than a preset of 2degree Celsius from its original temperature.

Alternatively, in another aspect of the present invention, there isprovided such an ultrasonic limited excitation device, preset for notheating any portion of the examined area with more than a preset of 3-4degree Celsius from its original temperature.

Alternatively, in another aspect of the present invention, there isprovided such an ultrasonic limited excitation device, preset for notexceeding ultrasonic energy output of spatial peak temporal-average(Ispta) of 720 mW/cm^2, and mechanical index of 1.9, or spatial peakpulse-average intensity (Isppa) of 190 W/cm^2.

Alternatively, in another aspect of the present invention, there isprovided such an ultrasonic limited excitation device, preset for notexceeding ultrasonic energy output of spatial peak temporal-average(Ispta) of 430 mW/cm^2, and mechanical index of 1.9, or spatial peakpulse-average intensity (Isppa) of 190 W/cm^2.

Alternatively, in another aspect of the present invention, there isprovided such an ultrasonic limited excitation device, preset for notexceeding ultrasonic energy output of spatial peak temporal-average(Ispta) of 94 mW/cm^2, and mechanical index of 1.9, or spatial peakpulse-average intensity (Isppa) of 190 W/cm^2.

Alternatively, in another aspect of the present invention, there isprovided such an ultrasonic limited excitation device, preset for notexceeding ultrasonic energy output of spatial peak temporal-average(Ispta) of 17 mW/cm^2, and mechanical index of 1.23, or spatial peakpulse-average intensity (Isppa) of 28 W/cm^2.

According to another aspect of the present invention there is provided asystem using ultrasonic backscattering waveform analysis ofultrasonically heated areas for medical imaging and/or determiningtissue type and/or irregularity and/or substance level in the tissue, orlikelihood of such a level, herein, also referred to as the ultrasoundexcited backscatter system, of the present invention, featuring the maincomponents of: (a) an ultrasonic heating device for differentiallyheating the examined tissue area; (b) an ultrasonic device, optionallyseparate from the ultrasonic heating device, for reading the spectralreflection of ultrasound from the tissue area, and/or the backscatterpattern and energy levels, across time as the temperature of the heatedtissue changes; (c) a process control and processing unit, or acontroller, operatively connected to the ultrasoundtransmitter/transmitters, for controlling the generation andtransmission of ultrasound waves, and to the diagnostics ultrasounddevice, for synchronizing between the two ultrasonic transmissions (theexciting ultrasound, and the diagnostics ultrasound), and for processingthe received ultrasonic waveforms and parameters in time, and analyzingdata and information (backscatter shift per location, backscatterenergy, etc.) generated before, while, and after the excitation, tooptionally generate a graph of coefficient levels across each positionin the examined area to generate a 2D, 3D, or 4D image of the examinedarea given the coefficients of each examined location in the examinedarea. The process control and data processing functions of the processcontrol and processing unit need not be performed by a single unit, butmay be distributed among two or more physically separate units, forexample separate units to control a heating ultrasound transducer, and adiagnostic ultrasound transducer, and to analyze data of backscattereddiagnostic ultrasound. Nevertheless, the separate units are collectivelyreferred to herein as a controller, or a process control and processingunit.

As will be described more particularly below, the invention enablesattaining one or more of the following advantages.

1. The use of an Ultrasound excited backscatter system enables accuratelocalization of a biopsy needle at the location of suspected malignanttissue, such that the sample is taken from an irregular substance withinthe organ.

2. Ultrasound excited backscatter system enables classification ofsuspected malignant tissue at the time of sampling.

3. The use of an Ultrasound excited backscatter system enables accuratelocalization of a brachytherapy needle at the location's of suspectedmalignant tissue, such that radioactive substance is placed at thesuspected malignant tissue.

4. The use of an Ultrasound excited backscatter system enables the2D/3D/4D imaging of soft tissue for any general radiology purposes.

There is thus provided, according to an exemplary embodiment of theinvention, a method for detecting abnormal tissue in a region of healthytissue, comprising:

a) making a first measurement of ultrasound backscattered from theregion;

b) heating the region, at least after the first measurement;

c) making one or more additional measurements of ultrasoundbackscattered from the region after some or all of the heating; and

d) analyzing the measurements to detect the abnormal tissue by findingdifferences in changes in temperature, caused by the heating, betweenthe abnormal tissue and the healthy tissue.

Optionally, the measurements and analysis are sensitive enough, and theheating causes a great enough temperature rise, to detect abnormaltissue 1 centimeter in diameter in its shortest dimension, which isheated by an amount that differs by a factor of 3 from the healthytissue.

Optionally, analyzing comprises calculating one or more characteristicsof a distribution of amplitudes of backscattered ultrasound as afunction of position from which it is scattered.

Additionally or alternatively, analyzing comprises calculating afrequency shift of backscattered ultrasound as a function of positionfrom which it is scattered.

Optionally, heating comprises heating with ultrasound.

Optionally, heating with ultrasound comprises using ultrasound generatedby a different ultrasound transducer than a transducer used to generatethe backscattered ultrasound measured in the first and additionalmeasurements.

Optionally, the method comprises not running the transducer used togenerate the ultrasound used for heating, while making the first andadditional measurements.

Optionally, heating comprises using ultrasound power that does notexceed spatial peak temporal-average (Ispta) of 720 mW/cm^2.

Optionally, heating comprises causing the temperature at each point inthe region to rise by no more than 4 degrees Celsius.

In an embodiment of the invention, analyzing comprises calculating atemperature change as a function of position in the region, as a resultof the heating, from the changes in the one or more ultrasoundbackscattering characteristics.

Optionally, the measurements are sufficiently sensitive so thatanalyzing the measurements can find differences in the temperaturechange, at different positions in the region, of less than 2 degreesCelsius, with a spatial resolution of 1 centimeter or better.

Optionally, the measurements are sufficiently sensitive so thatanalyzing the measurements can find the temperature change, as afunction of position in the region, to within 2 degrees Celsius, with aspatial resolution of 1 centimeter or better.

Optionally, making one of more additional measurements comprises makingat least two additional measurements, and analyzing comprisescalculating an ultrasound absorption rate and a thermal equilibrationrate as a function of position in the region.

Optionally, heating comprises heating with ultrasound power or RF poweror both, and the incident ultrasound power per area, or the incident RFpower per area, or both, is uniform to within a factor of 2 throughoutthe region, wherein the region has a cross-section of at least 3 cm by 3cm perpendicular to the direction of incidence of the power, and extendsover a distance of at least 1 cm in the direction of incidence of thepower.

There if further provided, in accordance with an exemplary embodiment ofthe invention, a system for detecting at least one type of abnormaltissue in a region of healthy tissue, comprising:

a) a diagnostic ultrasound transducer and detector;

b) a tissue heating element, the same as or different from thediagnostic ultrasound transducer, for heating tissue; and

c) a controller programmed to:

-   -   i) control the tissue heating element to heat the tissue in the        region;    -   ii) control the diagnostic ultrasound transducer and detector to        make at least two measurements of backscattered ultrasound from        the region, respectively before and after at least one time        interval when the tissue heating element is heating the tissue        in the region;    -   iii) analyze results of the measurements to find differences, at        different positions in the region, in the change in temperature        from before to after the time interval, that distinguish that        type of abnormal tissue from the healthy tissue; and    -   iv) using the differences to identify which parts of the region        are the abnormal tissue and which are healthy tissue.

Optionally, the tissue heating element comprises an ultrasoundtransducer, the same as or different from the diagnostic ultrasoundtransducer.

Optionally, the heating ultrasound transducer is different from thediagnostic ultrasound transducer.

Optionally, the controller is programmed to use the differences in oneor more characteristics of ultrasound backscattering before and afterthe time interval, to find differences in one or both of a heating rateof the tissue, and a temperature equilibration rate of the tissue.

Optionally, the controller is programmed to use the differences in oneor more characteristics of ultrasound backscattering to find differencesin both the heating rate of the tissue, and the temperatureequilibration rate of the tissue.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

Implementation of the method and/or system of embodiments of theinvention can involve performing or completing selected tasks manually,automatically, or a combination thereof. Moreover, according to actualinstrumentation and equipment of embodiments of the method and/or systemof the invention, several selected tasks could be implemented byhardware, by software or by firmware or by a combination thereof usingan operating system.

For example, hardware for performing selected tasks according toembodiments of the invention could be implemented as a chip or acircuit. As software, selected tasks according to embodiments of theinvention could be implemented as a plurality of software instructionsbeing executed by a computer using any suitable operating system. In anexemplary embodiment of the invention, one or more tasks according toexemplary embodiments of method and/or system as described herein areperformed by a data processor, such as a computing platform forexecuting a plurality of instructions. Optionally, the data processorincludes a volatile memory for storing instructions and/or data and/or anon-volatile storage, for example, a magnetic hard-disk and/or removablemedia, for storing instructions and/or data. Optionally, a networkconnection is provided as well. A display and/or a user input devicesuch as a keyboard or mouse are optionally provided as well.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1 is a schematic diagram of an apparatus with one form of anUltrasound Excited Backscatter System, according to an exemplaryembodiment of the invention; and

FIG. 2 shows a flowchart for a method of detecting abnormal tissue in aregion of healthy tissue, using ultrasound backscattering, according toan exemplary embodiment of the invention.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

An aspect of some embodiments of the invention concerns a method andsystem for the imaging or identification of tissue type or substanceand/or irregularities based on its behavior under ultrasonic heatingover time. The system includes an ultrasound resonator for differentialheating of different types of tissue, and the same or another ultrasonicdevice or machine measuring changes in ultrasonic backscatter over time,as a result of tissue heating. In addition, the system includes computeralgorithms analyzing ultrasonic backscatter patterns and gradients, as aresult of the heating in the examined area over time and location toimage the internal subregions of tissues in the examined area. Thesystem is built from single/multiple ultrasonic frequency transmitters,transmitting ultrasonic waves at certain frequency or frequencies,certain amplitude/amplitudes and energy levels. The exposed area isheated; it absorbs some of the ultrasonic energy, and as a result,changes its scattering behavior as a function of the location substancecomposition and the ultrasound waves mix the area is exposed to, and theduration of this exposure. The system measures ultrasonic backscatterwaveforms, their parameters and gradients as they change in time. Thecomputer algorithms compute each location's coefficients from thetransmitted ultrasonic parameters, the measurement of the backscattersignals, and their gradients in time. These coefficients may be used forimaging purposes, to compare the coefficients of each location againstthe other locations to determine irregularities, and/or to analyzebehavior of these coefficients to determine tissue types or substancecomposition or substance levels in the examined locations.

In some embodiments of the invention, instead of or in addition to usingbackscattering of ultrasound to detect changes in the tissue as a resultof heating, specular reflection of ultrasound from the tissue is used,for example as a result of differences in acoustic impedance in thetissue resulting from differential heating.

An aspect of some embodiments of the invention concerns a method ofdetecting abnormal tissue in a region of healthy tissue, using heatingof the tissue, and measurements of backscattering of ultrasound wavesfrom the tissue. Optionally, the to heating is done by ultrasound,either the same ultrasound used for backscattering measurements, orseparate heating ultrasound waves. Backscattering of ultrasound wavesfrom the region are measured at least twice, before and after theheating. There may also be additional heating before the firstmeasurement, and/or after the second measurement, and/or during themeasurements. The heating may cause abnormal and healthy tissue tochange in temperature by different amounts, between the twomeasurements. Different changes in temperature, in healthy and abnormaltissue in the region, can be distinguished by analyzing thebackscattered ultrasound from the region. This may be possible even ifthe backscattered ultrasound waves are not used, or are not usable, formeasuring the temperature or the temperature change absolutely. Thedifferent changes in temperature are used to detect the presence andlocation of the abnormal tissue in the region.

In some embodiments of the invention, changes in characteristics of thebackscattered ultrasound, before and after the heating, are useddirectly to detect the presence and location of abnormal tissue, evenwithout calculating any changes in the temperature. It should be notedthat heating of the tissue may cause changes in backscatteringcharacteristics of the tissue even without changing its temperature, forexample by causing a phase change in a component of the tissue. Althoughthe description herein generally refers to temperature changes caused bythe heating, it should be understood that any change in ultrasoundbackscattering characteristics, caused by heating, may be used insteadfor distinguishing abnormal tissue from healthy tissue.

Any of the methods or devices described herein, for distinguishingabnormal from healthy tissue, may also be used for distinguishing anydifferent kinds of tissue, including two different kinds of abnormaltissue, or two different kinds of healthy tissue, or more than twodifferent kinds of tissue.

As used herein, “finding differences” in temperature change, for examplefor two different locations in the region, includes not only finding theresult of subtracting one temperature change from the other, but alsoincludes detecting that there is a difference in two measuredtemperature changes, to a certain degree of confidence, even withoutsubtracting one from the other, and even if one or both of the measuredto temperature changes are sufficiently uncertain that it would not bevery meaningful or useful to subtract one from the other.

Different changes in temperature may occur in healthy and abnormaltissue, in response to exposure to heating, because the two types oftissue may be heated at different rates, and/or because the two types oftissue may equilibrate at different rates due to the body's naturalthermal equilibration mechanisms. For example, cancerous tissue mayequilibrate to body temperature more rapidly after it is heated thannormal tissue does, if it is more vascularized than normal tissue.Optionally, differences in heating rate are separated from differencesin thermal equilibration rate, by making three of more measurements ofbackscattered ultrasound at different times. For example, measurementsare made before heating, immediately after heating ends, and a fewminutes after heating ends, when some thermal equilibration hasoccurred. Alternatively, measurements may be made before heating, in themiddle of heating, and at the end of a heating interval that iscomparable to the thermal equilibration time. Measurements may also berepeated with different heating intervals or different heating power, toseparate heating rate from equilibration rate. Heating rates may becalculated, independently of thermal equilibration rates, by measuring atemperature change over a heating interval that is short compared to thethermal equilibration time. Alternatively, both heating rate and thermalequilibration rate may be calculated using a model for combined heatingand thermal equilibration, with the heating rate and thermalequilibration rate as free parameters, and fitting the model totemperature change measurements at three different times.

If heating is done by ultrasound, then the heating rate of the tissuedepends on its ultrasound absorption rate. Heating may also be done bymicrowaves, radio waves, infrared if it can penetrate far enough intothe body, or any other means known in the art, including immersion in aheating bath. Optionally, the heating is done by a means thatdistinguishes healthy from abnormal tissue, for example by ultrasound ata frequency which is absorbed at a different rate by the healthy and theabnormal tissue. Alternatively, even if heating is done by a means thatdoes not distinguish healthy from abnormal tissue, healthy tissue may bedistinguished from abnormal tissue by having a different thermalequilibration rate.

Optionally, the heating power, whether from ultrasound or anothersource, is distributed relatively uniformly throughout most of thetissue region being examined, so that differences in heating are duesubstantially to differences in absorption rate in the tissue, ratherthan being due mostly, or almost entirely, to non-uniform heating powerdistribution. For example, in the case of heating with ultrasound poweror RF power, the incident ultrasound power or RF power varies by lessthan a factor of 2, or less than 30%, or less than 20%, or less than10%, over the tissue region. Optionally, in a plane normal to theincidence of the power, the tissue region is at least 3 cm×3 cm, or atleast 5 cm×5 cm, or at least 10 cm×10 cm, in cross-section, and extendsover a distance, in the direction of incidence of the power, of at least1 cm, or at least 2 cm, or at least 5 cm, or at least 10 cm.

In some embodiments of the invention, instead of heating the tissue, itis cooled, optionally before any measurements are made of backscatteredultrasound. Consequent warming of the tissue to thermal equilibrium, asa function of position, is measured at at least two different times, byanalyzing measurements of backscattered ultrasound, and differences inthe thermal equilibration rate are used to distinguish the healthytissue from the abnormal tissue. The analysis need not calculatetemperatures at each time, but optionally uses changing characteristicsof the backscattered ultrasound directly to find thermal equilibrationtimes.

Optionally, if ultrasound heating is used, the ultrasound absorptionrate is calculated from the increase in temperature resulting fromapplying a given heating ultrasound heating power to the region, takinginto account a decrease in incident ultrasound power going across theregion in the direction of propagation of the ultrasound, due toabsorption and scattering of ultrasound as it traverses the tissue.Similar considerations apply if other types of waves are used forheating, such as microwaves.

Healthy tissue and abnormal tissue may be further distinguished byrepeating measurements using different frequencies of heatingultrasound, for which the ratio of absorption rate in healthy andabnormal tissue may differ, and a similar method may be used formicrowave heating or heating with other types of waves. Even if thebackscattered ultrasound is barely adequate for distinguishing thetemperature change in healthy and abnormal tissue, they may bedistinguished with more reliability if to differences between them aredetected using a plurality of different parameters, for exampleequilibration rate, and absorption rate at two or more differentultrasound frequencies.

Optionally, if the diagnostic ultrasound used for backscatteringmeasurements is separate from the heating ultrasound, in a case whereultrasound heating is used, then no heating ultrasound is used duringthe backscattering measurements, which has the potential advantage ofavoiding interference from reflected or scattered heating ultrasound inmeasuring the generally weaker signal from the backscattered diagnosticultrasound. Alternatively, if the ultrasound heating begins before atleast one of the measurements of backscattering, and continues afterthat measurement, then it is not interrupted for that measurement,though optionally it is reduced in power during the measurement.

Optionally, the measurements and analysis of backscattered ultrasoundare sensitive enough to detect a volume of abnormal tissue that is 1 cmin diameter in its shortest dimension, which increases in temperature byan amount that differs by a factor of 3 from normal tissue surroundingit, with 90% confidence for example. This sensitivity is optionallypresent when, for example for safety reasons, the maximum increase inlocal temperature in the region is kept below 4 degrees Celsius, orbelow 3 degrees, or below 2 degrees, or below 1 degree. This sensitivityis also optionally present when, for example for safety reasons, thepower of the heating ultrasound is kept below regulatory limits fordiagnostic ultrasound, for example below any of the power limits listedabove. Optionally, the measurements and analysis of backscatteredultrasound are sensitive enough to detect differences in temperaturechange, between the healthy and abnormal tissue, of less than 2 degreesCelsius, or less than 1 degree, or less than 0.5 degree. Optionally, themeasurements are sensitive enough to measure temperature changeabsolutely, in the abnormal tissue and/or in the healthy tissue, towithin 2 degrees, or 1 degree, or 0.5 degrees.

Optionally, the heating ultrasound, or heating power from anothersource, is used for a duration that is short compared to a typicalthermal equilibration time, or for an interval comparable to or greaterthan a typical thermal equilibration time in tissue. For example, theheating duration is less than 1 minute, or between 1 and 2 minutes, orbetween 2 and 3 minutes, or between 3 and 5 minutes, or more than 5minutes.

Optionally, the measurement of backscattered ultrasound comprisesmeasuring one or more characteristics, for example a standard deviation,of a distribution of amplitudes of backscattered power from differentclosely spaced locations in the heated region. Such measurements can beused to estimate temperature change, or at least to detect qualitativedifferences in temperature change from different parts of the region,using methods similar to those described by Arthur et al, cited above.Additionally or alternatively, the measurement of backscatteredultrasound comprises measurements of a shift in harmonic frequency ofultrasound scattered by a semi-regular lattice structure in the tissue,which can be used to estimate temperature, or at least to detectqualitative differences in temperature change from different parts ofthe region, using methods similar to those described by Seip and Ebbini,cited above. Optionally, both methods are used to estimate temperaturechanges from the backscattered ultrasound.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

Referring now to the drawings, FIG. 1 illustrates a system for medicalimaging of soft tissue. The system includes an Ultrasonic resonator (2)for heating tissues of the examined area of the patient (1). Theresonator (2) is connected to a transducer (3) which is attached to thebody of the patient (1), and induces ultrasonic power at a determinedwave mix of frequencies, amplitudes, and energy levels. As theultrasound waves propagate through the body tissues, their energy isabsorbed in the tissues as a function of the tissue type and substancecomposition. Each tissue type, changes its ultrasonic behavior, andspecifically its scattering behavior in response to the heating. Asecond ultrasound device (5), of diagnostic ultrasound characteristics,is connected to a second transducer (4), diagnosing the ultrasonicsignal from the examined area. As the tissues examined absorb theenergy, the backscatter pattern and energy of the diagnostic ultrasoundsignal may change, depending on the tissue type and/or substancecomposition at each location of the examined organ. A controller (6),for example a computer, calculates parameters at each location and timefrom the backscattering behavior related to that location, andaccordingly optionally displays in the display (7), to or another outputdevice, a 2D or 3D or 4D image of the diagnosed area. The displayoptionally identifies locations in the tissue that appear to beabnormal, or possibly abnormal, based on their backscattering behavior,including cancerous tissue for example. Controller (6) also optionallycontrols the timing and operating parameters of resonator (2) and/ordevice (5). In some embodiments of the invention, one or more of thedifferent functions of the controller are located in physically separateunits, but the units are still referred to collectively as “thecontroller.”

FIG. 2 shows a flowchart 200 for a method of detecting abnormal tissuein a region of healthy tissue, using ultrasound backscattering,according to an exemplary embodiment of the invention. At 202,ultrasound is scattered from the tissue, and the scattered ultrasound ismeasured at 204, and the results are analyzed and recorded at 206, forexample to provide an indication of the temperature as a function ofposition in the tissue. If the tissue has not already been heated, orthe heating has not been finished, then a decision is made at 208 toheat the tissue, or to further heat the tissue, at 210. Scattering ofultrasound from the tissue at 202, measuring the scattered ultrasound at204, and analyzing and recording the results at 206, are then repeatedafter the heating, or after the additional heating, when the temperatureis higher. Optionally these actions are repeated more than once, forexample to provide an indication of the change in temperature as afunction of position after different degrees of heating, or overdifferent time intervals. If the abnormal tissue has a different heatingrate than the healthy tissue, for example a different ultrasoundabsorption rate if the heating is done by ultrasound, then the abnormaltissue will generally undergo a different temperature change as a resultof the heating, than the healthy tissue, at least if the heating is doneover a time interval short compared to the thermal equilibration time.

If the heating is finished, then at 212 a decision is made as to whetherthe tissue has already been cooled, and if the cooling process hasfinished. If not, then at 214 the tissue is allowed to cool, or to coolfurther. Optionally, the tissue is cooled passively. Alternatively, thetissue is cooled actively. Scattering ultrasound from the tissue at 202,measuring the scattered ultrasound at 204, and analyzing and recordingthe results at 206, are repeated after the tissue has been allowed tocool. Optionally, these actions are repeated more than once, for exampleto measure the temperature as a function of to position for differenttime intervals relative to the thermal equilibration time. If theabnormal tissue has a different thermal equilibration rate than thehealthy tissue, for example because it has a different degree ofvascularization, then the temperature change during the cooling will bedifferent for the abnormal and healthy tissue.

If the cooling of the tissue has been completed, then at 216 the resultsof the measurements are outputted. For example, the results may show thetemperature as a function of position at two or more times before,after, and during the heating, as well as at two or more times before,after, and during the cooling. This information may be used, forexample, to find the ultrasound absorption rate and the thermalequilibration time of the tissue, as a function of position. Thatinformation, in turn, may make it possible to detect and/or characterizeabnormal tissue. For example, cancerous tissue may have a differentultrasound absorption rate, and a shorter thermal equilibration time,than normal tissue, due to different cellular composition and a greaterdegree of vascularization than normal tissue.

As used herein the term “about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”. This termencompasses the terms “consisting of” and “consisting essentially of”.

The phrase “consisting essentially of” means that the composition ormethod may include additional ingredients and/or steps, but only if theadditional ingredients and/or steps do not materially alter the basicand novel characteristics of the claimed composition or method.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

The word “exemplary” is used herein to mean “serving as an example,instance or illustration”. Any embodiment described as “exemplary” isnot necessarily to be construed as preferred or advantageous over otherembodiments and/or to exclude the incorporation of features from otherembodiments.

The word “optionally” is used herein to mean “is provided in someembodiments to and not provided in other embodiments”. Any particularembodiment of the invention may include a plurality of “optional”features unless such features conflict.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

What is claimed is:
 1. A method for detecting a tissue surrounded by adifferent tissue in a region, the method comprising: a) making a firstmeasurement of ultrasound backscattered from the region; b) heating theregion, at least after the first measurement, using incident ultrasoundheating power, RF heating power or both, causing the temperature of eachpoint in the region to rise by no more than 4 Celsius; c) making one ormore additional measurements of ultrasound backscattered from the regionafter some or all of the heating; and d) analyzing the measurements,using uniformity of the incident heating power to detect the tissue byfinding one or both of differences in changes in temperature anddifferences in thermal expansion, caused by the heating, between thetissue and the surrounding different tissue; wherein the region has across-section of at least 3 cm by 3 cm perpendicular to the direction ofincidence of the power, and extends over a distance of at least 1 cm inthe direction of incidence of the power.
 2. A method according to claim1, wherein the heating heats both a tissue in the region that is no morethan 1 centimeter in diameter in its shortest dimension, and a differentsurrounding tissue in the region, so that the two tissues expand due tothe heating by amounts that differ from each other, and the measurementsand analysis detect the different amounts of expansion, to distinguishthe two tissues.
 3. A method according to claim 1, wherein analyzingcomprises calculating one or more characteristics of a distribution ofamplitudes of backscattered ultrasound as a function of position fromwhich it is scattered.
 4. A method according to claim 1, whereinanalyzing comprises calculating a frequency shift of backscatteredultrasound as a function of position from which it is scattered.
 5. Amethod according to claim 1, wherein heating comprises heating withultrasound.
 6. A method according to claim 5, wherein heating withultrasound comprises using ultrasound generated by a differentultrasound transducer than a transducer used to generate thebackscattered ultrasound measured in the first and additionalmeasurements.
 7. A method according to claim 6, also comprising notrunning the transducer used to generate the ultrasound used for heating,while making the first and additional measurements.
 8. A methodaccording to claim 5, wherein heating comprises using ultrasound powerthat does not exceed spatial peak temporal-average (Ispta) of 720mW/cm^2.
 9. A method according to claim 1, wherein analyzing themeasurements finds differences in the temperature change, at differentpositions in the region, of less than 2 degrees Celsius, with a spatialresolution of 1 centimeter or better.
 10. A method according to claim 9,wherein the calculated differences in the temperature change, for atleast some different positions in the region, are accurate to withinless than 2 degrees Celsius, with a spatial resolution of 1 centimeteror better.
 11. A method according to claim 1, wherein making one of moreadditional measurements comprises making at least two additionalmeasurements, and analyzing comprises calculating an ultrasoundabsorption rate and a thermal equilibration rate as a function ofposition in the region.
 12. A system for detecting at least one type ofabnormal tissue in a region of healthy tissue, comprising: a) adiagnostic ultrasound transducer and detector; b) a tissue heatingelement, the same as or different from the diagnostic ultrasoundtransducer, for heating tissue; and c) a controller programmed to: i)control the tissue heating element to heat the tissue in the region byless than 4 degrees Celsius; ii) control the diagnostic ultrasoundtransducer and detector to make at least two measurements ofbackscattered ultrasound from the region, respectively before and afterat least one time interval when the tissue heating element is heatingthe tissue in the region; iii) analyze results of the measurements,usinguniformity of the heating power to find differences, at differentpositions in the region, in one or both of the change in temperature andthe thermal expansion , from before to after the time interval, thatdistinguish that type of abnormal tissue from the healthy tissue; andiv) using the differences to identify which parts of the region are theabnormal tissue and which are healthy tissue. wherein the tissue heatingelement comprises an ultrasound transducer, an RF antenna, or both, andthe tissue heating element is adapted to heat a region with cross-section of at least 3 cm by 3 cm perpendicular to the direction ofincidence of the power, and extending over a distance of at least 1 cmin the direction of incidence of the power.
 13. A system according toclaim 12, wherein the tissue heating element comprises an ultrasoundtransducer, the same as or different from the diagnostic ultrasoundtransducer.
 14. A system according to claim 13, wherein the tissueheating element is different from the diagnostic ultrasound transducer.15. A system according to claim 12, wherein the controller is programmedto use the differences in one or both of a heating rate of the tissue,and a temperature equilibration rate of the tissue. differences in oneor both of a heating rate of the tissue, and a temperature equilibrationrate of the tissue.
 16. A system according to claim 15, wherein thecontroller is programmed to use the differences in the temperaturechange to find differences in both the heating rate of the tissue, andthe temperature equilibration rate of the tissue.